Controlled-release melatonin compositions and related methods

ABSTRACT

A melatonin-containing product includes a composition comprising melatonin, a pH lowering agent, and a gel-forming forming polymer. When ingested, the composition forms an acidic aqueous gel matrix having melatonin dissolved therein for releasing melatonin into the intestines for a sustained time period.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation of application Ser. No. 13/359,638, filed Jan.27, 2012, which claims priority to provisional Application No.61/437,217, filed Jan. 28, 2011. Each of these prior applications isincorporated by reference in its entirety.

FIELD OF THE INVENTION

The invention relates to controlled-release melatonin compositions andrelated methods and, more particularly, to controlled-release melatonincompositions that include a controlled pH environment around themelatonin in the composition.

BACKGROUND

Melatonin is a hormone secreted by the pineal gland, a smallpinecone-shaped gland located near the center of the brain. Its chemicalformula is N-acetyl-5-methoxytryptamine, which is a derivative of theamino acid tryptophan and serotonin. The pineal gland secretes melatoninin a circadian rhythm—an approximately 24-hour cycle in the biochemical,physical or behavioral processes of an organism. A circadian rhythm isan endogenous, or built-in function, that is adjusted by environmentalstimuli, such as daylight. It is known that the body plasmaconcentration of melatonin is low during the daytime, starts to riseduring the late evening, and is maintained at 25-120 pg/mL during thenight (over 8 hours) until it returns to the daytime baseline (Lee,1995).

Exogenous, or synthetic, melatonin has been proposed to have clinicalpotential in human subjects to treat melatonin deficiency in theelderly, (Touitou, 2001) circadian rhythm disorders, including sleepdisorders, jet lag, shift work syndrome, and seasonal affective diseases(Lee, 1995). Some suggest that melatonin may also be effective in thetreatment of breast cancer, fibrocystic breast diseases, and coloncancer. Melatonin has been shown to modify the immune response, thestress response, certain aspects of the aging process, sleepdisturbances in Alzheimer's patients, and oxidative stress. Thissuggests a plethora of beneficial uses for melatonin.

Exogenous melatonin treatments encounter several problems. Melatonin iseliminated from the blood quickly once administered. It has a plasmaelimination half-life of less than one hour (Bénès, 1997). Whenadministered orally, it shows low and variable bioavailability (Bénès,1997). As with most oral administrations, it can take more than 30minutes after ingestion for the blood plasma concentration of melatoninto reach its peak. This is partly due to the need for release of themelatonin from the dosage form followed by permeation through the wallof the gastrointestinal tract (“G.I. tract”) for absorption to occurbefore the melatonin can enter the bloodstream.

Melatonin is slightly soluble, has good permeability characteristics,and is in the class II category according to the BiopharmaceuticsClassification System (Tran, 2009). Therefore, the amount of melatoninavailable for absorption into the bloodstream primarily depends on itssolubility. Melatonin's solubility generally decreases in less acidicenvironments. Because the pH of the gastrointestinal tract variessignificantly, different amounts of melatonin are available forabsorption into the bloodstream, depending on the region of the G.I.tract the melatonin enters.

Orally administered immediate and controlled-release melatoninformulations exist. Studies indicate large intersubject variability ofmelatonin in the blood plasma of human subjects given melatonin orally(Bénès, 1997). Other problems reported include poor oral bioavailabilityand a nutritional status effect on the oral bioavailability (Bénès,1997).

Various formulations of melatonin have been developed to provide releaseof melatonin over a 3 to 10 hour period to stimulate the natural (invivo) release of melatonin. These formulations have not gained wideacceptance because of their variable response in patients. Patients maytherefore experience middle of the night awakening, early morninggrogginess, and sleep times of less than 5 hours.

Alternatives to conventional oral controlled-release dosage forms alsoexist. For example, a hydroxypropyl methylcellulose (“HPMC”) matrixtablet was reported to release melatonin at a rate that was comparableto two commercially available products (Lee, 1999). In another example,the controlled-release characteristics of melatonin in a pH-responsiveamphiphilic hydrogel with interpenetrating polymer networks was reportedto be a function of the pH of the external environment of the tablet(Liu, 2006). Such controlled-release dosage methodologies remain intheir infancy.

Several references in the patent literature also address melatoninformulations. For example, U.S. Pat. No. 5,498,423 and U.S. PatentApplication Publication No. 2010/0119601, which are incorporated byreference herein, except to the extent that they are inconsistent withthis application.

SUMMARY

An aspect of the invention is directed to a controlled-release melatonincomposition that can be delivered to the GI tract and will release abioavailable amount of melatonin in the GI tract over the course of 6-8hours. This may be achieved by essentially insulating the melatonin fromthe variations in the GI tract's pH by coating the melatonin in amaterial that maintains an approximately constant pH around themelatonin, even when the pH of the GI tract changes.

One aspect of the invention is directed to a controlled-releasemedicament composition comprising melatonin dispersed in a controlledmelatonin release portion that comprises a polymer matrix. The polymermatrix is adapted to encapsulate the melatonin in a melatonin solubilityenhancing pH environment. Additionally, the polymer matrix is adapted tomaintain the melatonin solubility enhancing pH environment when thecomposition is located in a melatonin solubility diminishing pHenvironment, as is found in various regions of a mammalian G.I. tract,for allowing an effective amount of melatonin to be released into themelatonin solubility diminishing pH environment.

One aspect of the invention is directed to a controlled-releasemedicament composition comprising melatonin dispersed in a hydrogelmatrix having sufficient acidic moieties therein to maintain an acidicenvironment local to the melatonin when the melatonin is in agastrointestinal tract of a patient. This ensures that the compositionreleases melatonin into the plasma following administration to a humanpatient according to the endogenous melatonin profile (further describedherein).

One aspect of the invention is directed to a controlled-releasemedicament compositio comprising:

approximately 0.5% to 1.5% w/w of melatonin; approximately 2.0% to 7.0%w/w of PEG8000; approximately 3.0% to 40% w/w of citric acid;approximately 0.0% to 40.0% w/w of HPMC; and approximately 41.5% to94.5% binder; approximately 0-3% other excipients.

In a preferred embodiment of a controlled-release composition, thedosage form releases approximately 50% of the melatonin withinapproximately 1-3 hours after being administered to a patient andrelease approximately 50-90% of the melatonin for approximately 3-9hours after being administered to the patient.

One aspect of the invention is directed to a method of making acontrolled-release medicament composition, the method comprisingobtaining a composition comprising melatonin dispersed in a controlledmelatonin release portion comprising a polymer matrix, the polymermatrix adapted to encapsulate the melatonin in a melatonin solubilityenhancing pH environment and to maintain the melatonin solubilityenhancing pH environment when the composition is located in a melatoninsolubility diminishing pH environment for allowing an effective amountof melatonin to be released into the melatonin solubility diminishing pHenvironment. The method further comprises the step of preparing a dosageform from the composition that can be administered to a patient.

One aspect of the invention is directed to a method of making acontrolled-release medicament composition, the method comprising forminga solution comprising melatonin and a melatonin solubility enhancer;blending an acidic substance and a hydrogel forming polymer to form ablend; mixing the solution and the blend to form a wet blend; drying thewet blend to form a dried blend; and combining the dried blend with oneor more additional excipients to provide a dosage form.

One aspect of the invention is directed to method of making acontrolled-release medicament composition, the method comprisingobtaining a composition comprising melatonin dispersed in a controlledmelatonin release portion comprising a polymer matrix, the polymermatrix adapted to encapsulate the melatonin in a melatonin solubilityenhancing pH environment and to maintain the melatonin solubilityenhancing pH environment when the composition is located in a melatoninsolubility diminishing pH environment for allowing an effective amountof melatonin to be released into the melatonin solubility diminishing pHenvironment. This method additionally entails the preparing, from thecomposition, a dosage form that can be administered to a patient.

One aspect of the invention is directed to a method for treating apatient in need of, melatonin therapy, the method comprisingadministering an effective amount a controlled-release melatonincomposition of the invention the patient.

The previously summarized embodiments of the invention have manyadvantages. Some, but not all, of those advantages are listed here. Notall of these advantages are required by all embodiments of theinvention.

One advantage of the present invention is that the formulations allowmelatonin to be released in the GI tract regardless of the G.I. tract'spH. A controlled-release layer of the medicament composition effectivelyinsulates the melatonin from the external environment to ensure that themelatonin is released into a region of body that would otherwise not beacidic enough to sustain an effective release.

Further, medicament compositions of the invention are formulated torelease all of the melatonin within approximately 8 hours of ingestion.This can provide the user with a full night if sleep, while avoiding anylingering effects from additional melatonin being released the followingday.

These and other objects, aspects, and advantages will be betterappreciated in view of the drawings and following description ofpreferred embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-section diagram of an embodiment of acontrolled-release unit of the present invention;

FIG. 2 is a cross-section diagram of an embodiment of acontrolled-release unit of the present invention wherein the coating hasmore than one layer;

FIG. 3 is a diagram of an embodiment of a tablet of the presentinvention;

FIG. 4 is a cross-section diagram of an embodiment of a bi-layer tabletof the present invention;

FIG. 5 is a flow diagram illustrating an embodiment of a low sheargranulation process;

FIG. 6 is a graph of the dissolution profile of embodiments of melatonincompositions of the invention;

FIG. 7 is a flow diagram illustrating an embodiment of a high sheargranulation process for the manufacture of extended-release melatonintablets;

FIG. 8 is a graph of the dissolution profile of an embodiment of anextended-release melatonin tablet;

FIG. 9 is a graph of the particle size distribution of an embodiment ofa high shear granulated melatonin placebo blend; and

FIG. 10 is a graph of the nocturnal plasma profile of melatoninconcentration in a healthy adult human. This profile exemplifies theprofile to be substantially simulated in accordance with a preferredembodiment of the invention.

DETAILED DESCRIPTION OF EMBODIMENTS

In the Summary of the Invention above and in the Detailed Description ofthe Invention and in the accompanying drawings, reference is made toparticular features (including method steps) of the invention. It is tobe understood that the disclosure of the invention in this specificationincludes all possible combinations of such particular features. Forexample, where a particular feature is disclosed in the context of aparticular aspect or embodiment of the invention, that feature can alsobe used, to the extent possible, in combination with and/or in thecontext of other particular aspects and embodiments of the invention,and in the invention generally.

The term “comprises” is used herein to mean that other ingredients,steps, etc. are optionally present. When reference is made herein to amethod comprising two or more defined steps, the steps can be carried inany order or simultaneously (except where the context excludes thatpossibility), and the method can include one or more steps which arecarried out before any of the defined steps, between two of the definedsteps, or after all of the defined steps (except where the contextexcludes that possibility).

In this section, the present invention will be described more fully withreference to the accompanying drawings, in which preferred embodimentsof the invention are shown. This invention may, however, be embodied inmany different forms and should not be construed as limited to theembodiments set forth herein. Rather, these embodiments are provided sothat this disclosure will be thorough and complete, and will convey thescope of the invention to those skilled in the art.

The solubility of some pharmacologically active substances ispH-dependent. When such a pharmacologically active substance isadministered to a subject orally in a modified (sustained) releasedosage form, the pH in and around the dosage form will varysignificantly as the substance travels from the subject's mouth throughthe G.I. tract. As a result, the amount of the active substance releasedinto the G.I. tract for absorption will also vary.

Melatonin, for example, which has been reported to have a pKa ofapproximately 4.4 to 4.7, will have different degrees of dissociationand different solubilities as it travels through the G.I. tract of thesubject. In the gastric environment, at a pH range of approximately 1.0to 3.0, its solubility is relatively high. In the upper G.I. tractenvironment, at a pH range of approximately 4.5 to 5.5, its solubilitydecreases. In the lower G.I. tract environment, at a pH range ofapproximately 5.5 to 7.0, its solubility decreases even further. Thisvariability in the G.I. tract pH is not a major factor for conventionalimmediate-release dosage forms, as melatonin is readily dissolved in thelow pH of the gastric environment. Unfortunately, this results in themelatonin being absorbed and eliminated too quickly to mimic the patternof the endogenous melatonin found in healthy young subjects.

However, when a modified-release dosage form of melatonin is exposed tothe low pH gastric environment, the melatonin is readily soluble anddiffuses out of the dosage form at a faster rate due to a higherconcentration gradient in and around the dosage form. Unfortunately,when the modified release dosage form reaches a higher pH environmentfurther down the GI tract, the concentration gradient will be lower,resulting in a significantly lower release rate. Therefore, the factthat conventional immediate and modified release melatonin compositionshave a pH-dependent solubility profile means that there is variabilityin the release, absorption, and efficacy of the conventional melatonintreatments. The same is true for other active substances having asimilar pH-dependent solubility profile that need to be delivered viamodified release formulations.

One object of this invention is to provide a medicament composition thatis adapted to release an effective amount of an active ingredient withinthe pH range found in the intestines continuously for 3 to 10 hours.When melatonin is the active ingredient, the composition may be used totreat disorders such as, for example, melatonin deficiency, sleepirregularities or circadian rhythm irregularities.

A medicament composition in accordance with the present inventioncomprises of one or more active ingredients, such as melatonin, one ormore mechanisms for controlling the release rate of the melatonin, andcontrolled-release materials suitable for preparing a medicamentcomposition that can be administered to a subject as a dosage form. In aparticular embodiment, the controlled-release medicament compositionsare adapted to release melatonin over a period of 3-10 hours afteringestion regardless of the pH environment the medicament compositionencounters. Although melatonin is particularly useful in the invention,other active ingredients may include, but are in no way limited toRamelteon i.e.(S)—N-[2-(1,6,7,8-tetrahydro-2H-indenol{5,4-b}furan-8-yl)ethyl]propionamide,Agomelatine i.e. N-[2-(7-methoxynaphthalen-1-yl)ethyl]acetamide, andTIK-301 i.e. B-methyl-6-chloromelatonin. Medicament compositions can beformulated into any solid form, such as tablet, capsule, granule, orliquid form, such as a suspension.

As used herein, unless the context requires otherwise, the term“melatonin” includes melatonin and chemical derivatives of melatonin.

Besides the examples provided below, embodiments of a medicamentcomposition may comprise substances for the preparation of a finaldosage form. Examples of these substances include one or moreexcipients, diluents, disintegrants, solvents, processing aids,buffering agents, colorants, flavorings, solvents, coating agents,binders, carriers, glidants, lubricants, granulating agents, gellingagents, polishing agents, suspending agent, sweetening agent,anti-adherents, preservatives, emulsifiers, antioxidants, plasticizers,surfactants, viscosity agents, enteric agents, wetting agents,thickening agents, stabilizing agents, solubilizing agents,bioadhesives, film forming agents, essential oils, emollients,dissolution enhancers, dispersing agents, or combinations thereof.

Medicament compositions of the present invention may includecontrolled-released portions, expedited-release (burst) portions, orcombinations thereof. Either portion is designed to release an activeingredient within certain conditions and/or over a certain time frame.The delayed-released portion is formulated to release an activeingredient in the pH environment of the G.I. tract and, further, over acertain period of time. The expedited-release portion is formulated torelease an active ingredient into the upper digestive tract, such asinto the stomach, for example. The expedited release portion mayalternatively be achieved by tuning the size and shape of the dosageform to have enough surface area to release a desired amount of theactive ingredient within a desired period of time.

Referring initially to FIG. 1, a cross-section diagram of an embodimentof a controlled-release unit 10 of the present, invention is shown. Thecontrolled-release unit 10 in this embodiment may act as thedelayed-release portion in certain embodiments of the medicamentformulations. The controlled-release unit 10 includes at least oneactive unit 12 and one or more coatings 14. The coating 14 surrounds theactive unit 12 and contains at least one layer. In this embodiment thecoating 14 includes a controlled-release layer 16.

Referring to FIG. 2, a diagram of another embodiment of acontrolled-release unit 20 is shown. The controlled-release unit 20 inthis embodiment includes at least one active unit 12′ and one or morecoatings 14′. The coating 14′ includes two layers. One layer is acontrolled-release layer 16′. The other layer is a second layer 28. Thesecond layer 28 surrounds the controlled-release layer 16′.

Referring continually now to FIGS. 1 and 2, one having ordinary skill inthe art will recognize that each of these embodiments is merely shown asan example of certain embodiments. Details such as sizes, shapes,dimensions, relative dimensions and other details are not limiting. Morethan one active unit 12, 12′ can be contained within thecontrolled-release unit 10, 20. Controlled-release units 10, 20 may bein the form of multiparticulates or may be incorporated into a tablet.

The active unit 12, 12′ contains one or more active ingredients. In someembodiments, the active unit 12, 12′ contains a mixture of activeingredients. In some embodiments, the active unit 12, 12′ may alsocontain one or more inactive ingredients, including, but in no waylimiting, fillers, stabilizers, color coating, glidants and processingaids. Inactive ingredients and plasticizers can also be included in thecoating 14, 14′ or other portions of the medicament composition.

In the embodiment of FIGS. 1 and 2, the coating 14, 14′ may include asingle layer or multiple layers. At least one layer is acontrolled-release layer 16, 16′ which is adapted to provide a locallycontrolled pH environment around the active unit 12, 12′. Thecontrolled-release layer 16, 16′ is made of a material or combination ofmaterials that include acidic moieties therein. The coating 14, 14′ mayfurther include materials for making the medicament composition into adosage form such as a tablet, for example. In one embodiment, at leastone constituent of the controlled-release layer 16, 16′ is a materialcapable of forming a hydrogel. In another embodiment, at least onematerial in the coating 14, 14′ is an enteric coating material. In oneembodiment, at least one material in the coating 14, 14′ is a sealantcoating material.

In another embodiment, the controlled-release layer 16, 16′ is acombination of one or more polymers, one or more acidic molecules, oneor more acidic buffers or combinations thereof. The polymers can beselected from any number of pharmaceutically acceptable polymers such asthe celluloses (e.g., carboxymethylcelluloses, methylcelluloses,hydroxypropylcelluloses, hydroxypropylmethylcelluloses); hyaluronates;alginates; polysaccharides, heteropolysaccharides (pectins); poloxamers;poloxamines; ethylene vinyl acetates; polyethylene glycols; dextrans;polyvinylpyrrolidones; chitosans; polyvinylalcohols; propylene glycols;polyvinylacetates; phosphatidylcholines (lecithins); miglyols;polylactic acid; polyhydroxybutyric acid; mixtures thereof, copolymersthereof, derivatives thereof, and the like. Examples of dispersingagents include, but are not limited to, copolymer systems such aspolyethylene glycol-polylactic acid (PEG-PLA), polyethyleneglycol-polyhydroxybutyric acid (PEG-PHB),polyvinylpyrrolidone-polyvinylalcohol (PVP-PVA), and derivatizedcopolymers such as copolymers of N-vinyl purine (or pyrimidine)derivatives and N-vinylpyrrolidone.

Acidic molecules include organic and/or inorganic acidic molecules.Preferred organic acidic molecules include, but are in no way limitedto, low molecular weight carboxylic acids such as citric acid, succinicacid and tartaric acid. Preferred inorganic acidic molecules includephosphoric acid and hydrochloric acid, but these examples are in no waylimiting.

Acidic buffers can be prepared with organic or inorganic acidicmolecules. Acidic buffers such as mono sodium citrate or phosphoric acidmono potassium salt are provided as preferred examples, but acidicbuffers are in no way limited to these.

The controlled-release layer 16, 16′ provides a locally acidic pHenvironment at the active unit 12, 12′. The locally acidic pHenvironment ensures that an effective amount of the active ingredientwill be released continuously regardless of the external conditions. Oneparticular embodiment of the controlled-release layer 16, 16′ containsHPMC combined with one or more low molecular weight carboxylic acidmolecules.

The active unit 12, 12′, the controlled-release layer 16, 16′ or bothmay comprise a surfactant adapted to enhance the aqueous solubility ofmelatonin. Preferred surfactants include, but are not limited to,polyethylene glycol (PEG) based surfactants. The molecular weight of PEGcan be chosen to provide the desired properties of the composition. Inone preferred embodiment, PEG 8000 is used.

Referring now to FIG. 2 only, the second layer 28 surrounds thecontrolled-release layer 16′. The second layer 28 may be formulated tosuit many functions. It can be adapted for the preparation of themedicament composition into a dosage form, such as a tablet, capsule, orgranule, for example. Excipients used for forming such dosage forms areknown in the art and can be employed here for forming the second layer28. The second layer 28 may also be a seal coating formed from sealcoating materials known in the art. The second layer 28 may be anenteric coating formed from enteric coating materials known in the art.The second layer 28 may also comprise the expedited-release portion ofthe medicament formulation, which includes an active ingredient such asmelatonin.

Embodiments of the present invention provide controlled and extendedrelease medicament compositions containing melatonin as the activeingredient. One embodiment provides a sustained release of melatoninover a period of 3 to 10 hours in a manner that is reliable and notoverly dependent of the pH found in the lumen of various sections of theG.I. tract. In this case, the controlled-release layer 16, 16′effectively insulates the melatonin in the active unit 12, 12′ from thepH environment of the G.I. tract. Instead of dissolving directly intothe G.I. tract, the melatonin dissolves within the controlled-releaselayer 16, 16′ forming a concentration gradient across thecontrolled-release layer 16, 16′. Melatonin will then be released intothe G.I. tract from the periphery of the controlled-release layer 16,16′ in this manner. This will ensure that the desired concentrationgradient of the melatonin is maintained, irrespective of the pH of thelumen in the G.I. tract. The higher concentration of melatonin in theactive unit(s) 12, 12′ of the controlled-release unit 10, 20 willprovide for a predictable release from the medicament composition.

Another aspect of certain embodiments is to provide a controlled-releasemedicament composition comprising an active ingredient combined with apH lowering acid or acidic buffer, in a release controlling hydrogelmatrix. In this embodiment, the medicament composition can beadministered in a dosage form such as a tablet. The tablet can either becoated or not coated. To achieve this aspect of the invention,controlled-release units 10, 20 can be mixed with tableting materialsinto a tablet dosage form.

Referring to FIG. 3, a tablet 30 according to one embodiment of thepresent invention is shown. The shape of the tablet 30 is not limitingin any way. In one embodiment, a medicament composition comprises atablet containing tableting materials, one or more active ingredients, apH lowering acid or acidic buffer or combinations thereof and a hydrogelmatrix. As an example, the tablet 30 can contain the controlled-releaseunits 10, 20 according to the embodiments of FIGS. 1 and 2 orcombinations thereof. The tablet 30 can also include one or morecoatings (not shown) such as, by way of example only, an entericcoating, a seal coating, or combinations thereof.

In one embodiment of a tablet 30, an extended release formulationcomprises melatonin, PEG8000, and citric acid. The PEG8000 aids inmelatonin solubility and the citric acid creates a local environmentwith a pH lower than the pKa of melatonin. By keeping the pH of thelocal environment below the pKa of melatonin, melatonin is driven fromthe composition, preferably within, 9 hours of ingestion so that patientdoes not feel lingering effects of melatonin after the nocturnal period.In vivo, the lower G.I regions of high pH will not markedly adverselyaffect the solubility (and resultant release) of melatonin in such anextended release formulation due to the local acidic environment inwhich the melatonin is carried.

Besides tablets, other medicament formulations are multiparticulateformulations comprising an active ingredient combined with a pH loweringacid or acidic buffer, in a release controlling hydrogel matrix. In thisembodiment, the medicament composition can be administered in a dosageform such as a capsule by loading the multiparticulates into the capsuleor combining them with tableting materials.

Variable dose medicament compositions according to embodiments of thepresent invention will now be described. For example, medicamentcompositions can be formulated to provide an initial dose of melatoninto induce sleep, followed by a sustained release of melatonin over thenext 3 to 10 hours in a manner that is reliable and not overly dependentof the pH found in the lumen of various sections of the G.I. tract. Therelative dosage percentage of the burst and the sustained releaseportion can vary. In some embodiments, the initial burst is up to 65% ofthe dose. In other embodiments, the sustained release portion is up to90% of the dose. In one particular embodiment, the burst dose isapproximately 50% of the melatonin in the formulation, which is releasedapproximately in the first two hours after ingestion, and the sustainedrelease portion is the remaining 50% of melatonin, which is releasedapproximately over the next 5-8 hours. The rate of release can becontrolled in several ways. The concentration of the active ingredient,such as melatonin, in the active unit 12, 12′ can be adjusted. The pH ofthe containment layer 16, 16′ can be adjusted by adding more or feweracidic moieties. The thickness of the coating 14, 14′ can be adjusted. Arelease-rate controlling film/membrane or a hydrogel matrix of a unitdosage form, like a tablet, can also be incorporated to control therelease rate. If a tablet form is the final dosage form, the size andshape of the tablet can be adjusted to provide the preferred burst dose.

One variable dose medicament formulation according to an embodiment ofthe present invention provides a controlled-release medicamentcomposition comprising a controlled-release portion and an expeditedrelease portion. The controlled-release portion may includecontrolled-release units 10, 20, such as those shown in FIG. 1 or 2 orcombinations thereof. The expedited release portion may be part of thecontrolled-release units 10,20, such as the second layer 28 of thecontrolled-release unit 20 in FIG. 2. Alternatively, the expeditedrelease portion can be part of a tablet, such as the tablet 30 shown inFIG. 3. The expedited release portion can also be part of a bi-layertablet.

FIG. 4 shows a cross-section of a bi-layer tablet 40 according to oneembodiment of a melatonin medicament formulation, wherein the bi-layertablet includes a controlled-release portion 42 and an expedited releaseportion 44. The expedited release portion is formulated to provide aninitial burst dose of melatonin.

One embodiment of a variable dose medicament formulation includesmelatonin in combination with a local pH lowering acid or acidic bufferalong with a release controlling polymer, in the form of a tablet. Thetablet is formulated so that between 10% to 50% of the melatonin isreleased from the expedited release portion within approximately 1-3hours in an acidic dissolution medium and the remaining 50% to 90% ofthe melatonin in the delayed portion is released over the next 3 to 9hours approximately.

In one embodiment, the bi-layer tablet 40 is formulated such that theexpedited release portion contains from 10% to 50% melatonin, which isreleased within approximately 1-3 hours in an acidic dissolution medium.The controlled-release portion contains the remaining part of themelatonin in combination with a local pH lowering acid or acidic bufferalong with a release controlling polymer, where the remaining portion ofthe melatonin (i.e. 50% to 90%), which is in the controlled-releaseportion, is released over the next 3 to 9 hours approximately.

Another embodiment provides a variable dose medicament compositioncomprising melatonin in combination with a local pH lowering acid oracidic buffer and a coating, having at least a first coating layerwherein the first coating layer maintains a low pH inside thecontrolled-release unit and also serves as a release rate controllingmembrane. The coating may further include a second coating layer thatcontains a portion of the melatonin. The second coating provides anexpedited release of the melatonin.

FIG. 10 illustrates the average normal human plasma melatonin levelsthroughout the body as a function of time and is derived from (McIntyre,1987), which is incorporated by reference herein in its entirety. Theillustrated rise and decline of circulating melatonin occurs aftersunset and before sunrise, respectively. Maximal melatonin levels in aperson with a normal melatonin profile are typically about 60±20 pg/ml.In order to affect the brain by exogenous melatonin, it is desirable toelevate the plasma melatonin concentration so as to simulate the amountspresent at night in the brain of a person with a normal endogenousmelatonin profile. It is therefore desirable for embodiments of anextended release melatonin formulation to, upon administering such aformulation to a human subject, to achieve a rapid melatonin rise (1-2hours) in plasma melatonin concentration that plateaus at aconcentration of 60±20 pg/ml for about 6 to 7 hours, followed by a rapidmelatonin decline (1-3 hours) of plasma melatonin to about pre-riselevels.

Referring to FIG. 2, the first coating layer can be thecontrolled-release layer 16′. The second coating layer can be the secondlayer 28. In this embodiment, the controlled-release unit forms avariable dose granule. In alternative embodiments, the expedited releaseportion may be provided in combination with the coated granule as apowder blend.

Accordingly, many different variable dose melatonin medicamentformulations can be prepared. Several specific examples will now beprovided, however, these examples are not an exhaustive list.

An embodiment of a variable dose medicament formulation includes abi-layer tablet 40 containing controlled-release units 10.

Another embodiment of a variable dose medicament formulation includes atablet 30 containing controlled-release units 10 wherein the expeditedrelease portion is formulated into the tablet 30. Another embodiment ofa variable dose medicament formulation includes a tablet 30 containingcontrolled-release units 20, wherein the expedited release portion isthe second layer 28.

Another embodiment of a variable dose medicament formulation includes acapsule loaded with controlled-release units 20 in a granular form,wherein the expedited release portion is the second layer 28.

Another embodiment of a variable dose medicament formulation includes abi-layer tablet 40 containing controlled-release units 20.

Other embodiments of variable dose medicament formulation includecombinations of controlled-release units 10 and controlled-release units20 prepared into tablet 30, bi-layer tablet 40 or capsule dosage forms.

According to another aspect of the invention, methods of makingmelatonin medicament compositions according to embodiments of thepresent invention will now be described. The methods may be embodied inmany different forms. Only certain embodiments are described below byway of example.

In general, melatonin medicament compositions can be made in manydifferent ways. These include wet granulation processes, such as aqueousgranulation processes, or dry granulation processes, where dry powderbased blending process is followed by direct compression, or with anintermediate roller compaction step or a combination thereof.

One general embodiment of the method for making a melatonin medicamentcomposition comprises dry blending the active ingredient with at leastone polymer suitable for forming the controlled-release layer 16, 16′and conventional processing aids plus optional fillers. Conventionalprocessing aids include but are in no way limited to magnesium stearate,stearic acid, talc, sodium lauryl sulfate. Optional fillers include butare in no way limited to complex silicates, calcium carbonate, glycine,dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate,lactose, kaolin, mannitol, sodium chloride, talc, dry starches andpowdered sugar. The optional binder may be selected from among knownbinders, including, but not limited to, cellulose, and povidone, amongothers. In one embodiment, the binder is selected from amongmicrocrystalline cellulose, crospovidone, and mixtures thereof. The dryblend can then be formed into a typical dosage form for oraladministration. In a preferred embodiment, at least one of the polymersforms a hydrogel.

In a more particular embodiment, the method for making a melatoninmedicament composition comprises dry blending melatonin with the powderform of an acidic compound or acidic buffer, HPMC and, optionally,conventional processing aids and fillers. The dry blend can then bedirectly compressed into a typical tablet dosage form for oraladministration.

In order to prepare a solid dosage form such as a tablet, excipientsknown in the tableting arts can be employed.

In one embodiment, melatonin and/or one or more other active ingredientsare provided as a combination of an expedited release portion plus acontrolled-release portion. The expedited release portion may be presentas a coat, powder, or as a readily dissolvable amount of activeingredient on the surface of the controlled-release portion. Here, thecontrolled-release portion comprises melatonin plus one or more activeingredients in combination with an acidic compound or acidic buffer.

This composition allows for targeted release of melatonin and one ormore active ingredients from the expedited release portion into theacidic gastric environment of the patient and for targeted release ofthe melatonin and one or more active ingredients from thecontrolled-release portion into the lower gastrointestinal tract; forexample into the small intestine, the large intestine, the colon and/orthe rectum. In certain embodiments, the controlled-release portioncomprising the active ingredient further includes an enteric orpH-dependent coating such as cellulose acetate phthalates and otherphthalates. Examples include, but are in no way limited to polyvinylacetate phthalate, methacrylates, and Eudragit® polymers. Alternatively,the controlled-release portion provides controlled-release to the smallintestine and/or colon by the provision of pH sensitive methacrylatecoatings, pH sensitive polymeric microspheres, or polymers which undergodegradation by hydrolysis. The controlled-release composition can beformulated with hydrophobic or gelling excipients or coatings. Colonicdelivery can further be provided by coatings which are digested bybacterial enzymes such as amylose or pectin, by pH-dependent polymers,by hydrogel plugs swelling with time (Pulsincap), by time dependenthydrogel coatings and/or by acrylic acid linked to azoaromatic bondscoatings.

In certain embodiments the controlled-release portion compriseshypromellose (HPMC), microcrystalline cellulose, and a lubricant. Themixture of melatonin, an acid or acidic buffer, hypromellose andmicrocrystalline cellulose may be formulated into a tablet or capsulefor oral administration. In certain embodiments, the mixture isgranulated and pressed into tablets.

In other embodiments, the controlled-release portion of the presentinvention is provided in a multiparticulate formulation. A mixture ofmelatonin in combination with an acidic compound or acidic buffer plus asuitable polymer is granulated to form pellets which are coated.

In certain embodiments, the pellets are seal coated with anon-functional coating. In other embodiments, the pellets are first sealcoated with a non-functional coating and then coated with a functionalcoating.

As used herein the term “non-functional coating” is a coating that doesnot affect the release rate of the drug. Examples of a non-functionalcoating include hydroxypropyl cellulose, hypromellose or polyvinylalcohol. In certain embodiments, the non-functional coating is Opadry®Clear, which contains, hydroxypropyl methylcellulose and polyethyleneglycol.

As used herein, the term “functional coating” is a coating that affectsthe release rate of the drug from the dosage form. Examples of afunctional coating include ethylcellulose and polymethacrylatederivatives (Eudragit® polymers).

Accordingly, another embodiment provides a mixture of multiparticulateformulations, comprising pellet cores containing the active ingredientin combination with an acidic compound or acidic buffer plus anon-functional seal coating serving as the expedited release portionmixed with seal coated cores which have been further coated a functionalseal coating for controlled-release.

In the embodiment for the multiparticulate formulations, the expeditedrelease portion may be part of the functional seal coated formulation asa free flowing powder blend containing the active ingredient or it iscoated on the surface of the functional coat.

Certain embodiments of methods of using of the melatonin medicamentcomposition will now be described. These methods may be embodied in manydifferent forms. Only certain preferred embodiments are described below.

In one embodiment of the method of use, an effective dose of a melatoninmedicament composition comprising at least one controlled-release unit,such as a controlled-release unit 10,20 shown in one or more of theembodiments of FIGS. 1 through 4, is administered to a subject in needthereof.

In another embodiment of the method of use, an effective dose of amedicament composition comprising at least one controlled-release unit,such as a controlled-release unit 10,20 shown in one or more of theembodiments of FIGS. 1 through 4, is administered to a subject in needthereof. In this embodiment, the active unit 12, 12′ contains melatonin.

In another embodiment of the method of use, an effective dose of amedicament composition comprising at least one controlled-release unit,such as a controlled-release unit 10,20 shown in one or more of theembodiments of FIGS. 1 through 4, is administered to a subject in needthereof. In this embodiment, the active unit 12, 12′ contains at leastmelatonin and at least one or more of the following substances: HPMC,citric acid, monosodium citrate, tartaric acid, monosodium tartrate,phosphoric acid, and monosodium phosphate.

In another embodiment of the method of use, an effective dose of amedicament composition comprising at least one controlled-release unit,such as a controlled-release unit 10,20 shown in one or more of theembodiments of FIGS. 1 through 4, is administered to a subject in needthereof. In this embodiment, the active unit 12, 12′ contains at leastmelatonin and at least one or more of the following substances: HPMC,citric acid, monosodium citrate, tartaric acid, monosodium tartrate,phosphoric acid, and monosodium phosphate. Here, the medicamentcomposition is administered to a subject as a sleep aid.

In another embodiment, the method of use comprises administering and/oringesting a melatonin medicament composition of the present invention,permitting a part of the active ingredient(s) to be released in thestomach and allowing the melatonin medicament composition to enter thesmall intestine and permitting the remaining active ingredient(s) to bereleased into the small intestine in a controlled manner.

In another embodiment, the method of use comprises administering and/oringesting a melatonin medicament composition of the present invention,allowing the melatonin medicament composition to enter the smallintestine, and permitting the active ingredient(s) to be released intothe small and/or large intestine in a controlled manner.

An effective amount of melatonin is a quantity sufficient to affect acondition in the subject, such as affecting sleep, a disease, or processin the body of the subject. In some preferred embodiments, an effectiveamount can vary from 5 micrograms to 10 milligrams of melatonin.

EXAMPLES

This section describes a few specific examples of multiparticulateformulations of the invention and the methods by which they were made.These examples are presented by way of example only and are not intendedto limit the scope of the invention.

1. Preparation of a Tablet Medicament Formulations

A. Experimental Details.

Melatonin (Nutri-Force, lot number 81120) was used in the followingexperiments. The melatonin was reported to be a micronized grade.Shipment, handling and processing of melatonin and prototypes were allunder ambient room temperature. In-process materials and bulk tabletswere stored in double polyethylene bags with desiccant. Melatonin wasevaluated for appearance and particle size by sieve analysis.

Melatonin was visually characterized as a white to off-white poorflowing, fine powder. The particle size sieve analysis of melatoninrevealed a non-Guassian distribution of particles predominately of 150microns. Manufacture of the melatonin controlled-release tabletsdissolves the melatonin in a solution of polyethylene glycol and wateras part of the granulation fluid. Therefore, the particle size of themelatonin has no substantial effect on the final properties of thetablet, but did influence the rate at which the melatonin was dissolvedduring manufacture.

The following equipment was used preparing the formulations: KitchenAide planetary mixer; hot plate/magnetic stirrer; #6, 20 and 40 meshsieves; tray drying oven; comil with 0.039″ round hole screen; PiccolaB/D 8 station R&D press 0.455″×0.190″ capsule shaped tooling; ComputracLOD instrument; tablet hardness tester; tablet friability tester; andcalipers.

B. Development of 2 mg Melatonin Controlled-Release Tablets.

This section describes the development of prototype tablets inaccordance with the invention. A hypromellose based monolithic tabletwas utilized to achieve the targeted 6-8 hours extended release of the 2mg melatonin. The formulation was varied as presented in Table 1 toidentify a formulation with the targeted release profile. The tabletsize was held constant throughout the experimentation at 250 mg with astrength of 2 mg melatonin per tablet. The formulations were prepared insmall 200-300 g batches.

It was discovered that hypromellose exhibited undesirable flowcharacteristics. For this reason, a granulation process was used. Theprototypes were manufactured using a low shear wet granulation processin a planetary mixer. The intra-granular components were charged to themixing bowl and granulated either with water in the early prototypes ora solution of water, polyethylene glycol and melatonin in the laterprototypes. The wet granulation was wet milled through a 6 mesh handsieve to break up any large agglomerates and then oven tray dried at 60°C. to a ˜1-3% moisture level. The dried granulations were milled to sizewith a Comil cone type mill using a 0.55″ screen initially and later a0.039″ screen. The extra-granular excipients were bag blended into themilled granulation and the final blend was compressed on a Piccolatablet press using 0.455″×0.190″ capsule shaped tooling to a tabletweight of 250 mg and hardness of ˜5 kp. The process used for the leadprototype lot CYV45-002-048A is summarized in the flow diagram of FIG.5.

Analysis of Prototypes. A two stage dissolution procedure in a USPdissolution apparatus type III with 2 hour in 0.1 N hydrochloric acidfollowed by 12 hours in pH 6.8 phosphate buffer was used to evaluate theprototypes. This was later simplified to a single stage procedure in0.9% saline when the two methods were shown to give equivalent results.Melatonin assay and related substance testing was performed by HPLC onthe identified lead prototype, which was CYV45-002-48A.

Four different matrix forming hypromellose grades of varying molecularweight (K4M, K15M, K100LV and E50) were initially screened (LotsCYV45-002-004, 007, 011 and 012) as presented in Table 1. Thehypromellose E50 hypromellose proved to be the most promising of thepolymers evaluated, but it still released the melatonin slower thandesired. The dissolution results are presented in FIG. 6.

Citric acid was first included in the formulation at a concentration of16% but was increased to approximately 30% to maintain a low pH in thetablet matrix, enhancing the aqueous solubility of the melatonin.StarCap 1500 starch was initially added at a concentration 28% but wasreduced to 12% to make room for the added citric acid without increasingtablet size.

The aqueous solubility of the melatonin was further increased, bydissolving the melatonin in a 50% solution of polyethylene glycolsurfactant (PEG 3350) and spraying the solution into the granulation.The use of the PEG 3350 successfully increased the dissolution rate.

Concurrently, the effect of granulation particle size on the dissolutionwas evaluated by using a Quadro Comil with either a 0.055″ or 0.039″round hole screen (lot CYV45-002-021A and B). The particle size of thegranulation had little effect on dissolution rate but the smallerparticle size granules was observed to generate less inter-tabletvariability in the dissolution data. As a result, the use of the 0.039″screen was adopted for use in subsequent trials.

It was discovered that compression of the tablets with the PEG 3350 wasnot ideal. Sticking in the cups of the tablet punches was noted causingcosmetic defects, erratic tablet weight and hardness. To alleviate thesticking problem, higher molecular weight PEG 8000 was substituted forthe use of the PEG 3350 in the formulation (lot CYV45-002-030).

The batch was also scaled up to a 1 kg size and processed using a highshear granulator and fluid bed in place of the low shear planetary mixerand tray drying oven used previously. This was done to provide amplematerial to compress for an extended period to investigate the tabletsticking issue and adapt the process to be more suitable for futuremanufacturing. The scaled up process is summarized in the flow chart ofFIG. 7. The equipment used in the scaled up process included thefollowing: Fielder PP1 High Shear granulator; Niro-Aeromatic MP-1Multi-processor; Fitzmill J mill equipped with a 0.040 round holescreen; 2 Qt PK Blender; Piccola Eight Station B/D tablet press;0.1920″×0.4570″ capsule shape tooling embossed with “REM” embossed inupper punch; Accela-cota model 24MK III (24″ coating pan; hot plate;Overhead mechanical lab stirrer and propeller; and 20 mesh, 6 mesh and40 mesh sieves.

The tablets were also film coated with an Opadry II Blue non-functionalcoating to simulate the eventual final product that was desired. Thegranulation, blend and tablets processed well at the increased scaleusing the high shear granulation process. The sticking problem duringtablet compression was alleviated. Coating was conducted successfullywith no difficulties. It was discovered that melatonin dissolution wasundesirably retarded by the substitution of PEG 8000 for PEG 3350.Accordingly, the formulation was tweaked to optimize the melatonindissolution.

To compensate for the slower release of melatonin, a small trialformulation with PEG 8000 (lot CYV45-002-048B) was made shifting aportion of the intra-granular citric acid to extra-granular to increasedissolution by increasing the porosity of the tablet matrix. Also, asmall trial batch (lot CYV45-002-048A) utilizing the PEG 8000 butreducing the concentration of the matrix forming polymer hypromelloseE50 from 30% to 20% was made and evaluated. The tablet weight was heldconstant by adding additional extra-granular ProSolv which alsoincreased the hydrophilicity of the tablet to accelerate the release ofthe melatonin. Both approaches increased dissolution rate. LotCYV45-002-048A with reduced level of E50 (20%) best fit the targetdissolution profile (FIG. 8). Table 2 lists the ingredients in thisformulation.

The physical properties of the final blend and compressed tablets forthe CYV45-002-048A prototype are presented in Tables 3 and 4 and FIG. 9.The particle size of the final blend is non-Guassian and somewhatbi-modal. The flow of the final blend was acceptable as indicated by ablend compressibility of 14% and Flodex critical orifice value of 16 mm.The formulation is preferably compressed with tablet presses utilizing apaddle feeder to ensure good flow and ensure that particle sizesegregation does not occur in the press feed frame.

The compressed tablets had low tablet weight variation. Tablet hardnessand thickness also exhibited low variability. The mean tablet hardnesswas 3.9 kp with a range of 3.4-4.2 kp. At first glance, this wouldappear to be low tablet hardness; however, this provided a robust tabletwith extremely low friability (0.03% lost in 100 drops) suitable forcoating in a tablet coating pan. Because the tablets comprised both PEGand citric acid, the tablets were soft due to plastic deformation;however, this softness is advantageous as it imparts a high degree ofimpact resistance. The capsule-type shape of the tablets itself with alow cross-sectional area generates deceptively low tablet hardnessvalues.

Prototype Lot CYV45-002-048A was assayed for melatonin and relatedsubstances and the results are presented in Table 5. The high assayvalue of 105.2% can largely be explained as a result of loss of moistureduring the granulation drying process. The excipients and melatoninprior to granulation contained 5.1% moisture as determined in a baselineloss on drying evaluation but only contained 1.2% after the granulationwas dried; thereby, making the granulation 3.9% super-potent. Thegranulation moisture will preferably be dried to level approximate tothe baseline moisture in future batches.

Because maintaining a low pH in the tablet matrix over the course of therelease was a desired property, tablets of CYV45-002-048A were placed indissolution baths containing saline for up to 7 hours at 50 rpm paddlespeed. The “ghost” cores remaining after 7 hours were decanted away andpH of the tablet cores was determined. At 4 hrs the pH was determined tobe 2.5 and at 7 hrs it was 2.8. This indicates that citric acid remainedin the tablet for an extended period of time to lower the pH and assistin the solubilization of the melatonin.

Preparation of Final Tablet. The formulation development activitiessuccessfully identified a controlled-release prototype for 2 mg dosestrength melatonin tablet. The in-vitro dissolution release profile metthe desired objective of releasing half the melatonin with 1-2 hoursfollowed by first order release with greater than 90% release achievedat 6 hours. The release of melatonin was shown to be independent of thepH of the dissolution media with similar profiles generated using anacid/pH 6.8 two stage dissolution versus a single stage saline method.The in-vitro dissolution data suggests the tablets will releasemelatonin quickly to induce sleep and maintain a level of melatonin forup to 6 hours with little melatonin remaining to create grogginess uponawakening. The formulation utilizes GRAS excipients and can bemanufactured by a high shear wet granulation process suitable formanufacture in a production facility.

Using the experimental results described above, a final tabletcomprising melatonin was prepared. The final tablet comprises theingredients shown in Table 6 and was prepared according to the procedurethat will now be described.

A granulation solution was first prepared by:

-   (a) charging 58.0 g of purified water to a beaker and heating to    approximately 60° C.;-   (b) stirring and dissolving 50.0 g of PEG 8000 in the solution of    (a);-   (c) dissolving 8.0 g of melatonin in the solution of (b), resulting    in a clear amber solution; and-   (d) allowing the solution of (c) to cool to room temperature.

High shear wet granulation and wet milling was next performed by:

-   (a) screening the microcrystalline cellulose, citric acid and    hypromellose through a 20 mesh sieve and charge to a Niro PP-1 high    shear granulator;-   (b) mixing the materials in the granulator for approximately three    minutes at a speed of 300 rpm;-   (c) continued mixing and sprayed the granulation solution on the    mixing materials over the course of about 3 minutes;-   (d) while continuing mixing, spraying and additional 157 g of water    over the course of approximately 5 minutes;-   (e) wet massing the granulation by mixing and additional 2-3    minutes; and-   (f) discharging the product of (e) from the granulator and sizing    the granulation through a 0.156″ square hole screen using a Quadro    Comil.

Drying granulation and dry milling was next performed by:

-   (a) charging the wet milled granulation to a Niro MP-1 fluid bed    dryer and drying at an air inlet temperature of 60° C.;-   (b) drying the product of (a) to approximately 2% moisture content    (as determined by an LOD loss on drying instrument—the drying time    was approximately 25 minutes);-   (c) passing the product of (b) through a Fitzmill J mill at a slow    speed in the knives forward mode using a 0.040″ round hole screen

Final blending was achieved by:

-   (a) charging the dried milled granulation to a 2 quart V-blender;-   (b) screening the Cabosil colloidal silicon dioxide through a 20    mesh sieve and charging to the blender;-   (c) blending the product of (b) for 120 revolutions;-   (d) screening the magnesium stearate through a 40 mesh sieve and    charging to the blender; and-   (e) blending the product of (d) for 72 revolutions.

The final blend was compressed into a tablet by:

-   (a) equipping a Piccola BD 8 station rotary tablet press with    0.1920″×0.0.4570″ capsule shaped tablet tooling;-   (b) loading the tablet press with the final blend; and-   (c) compressing tablets to the following targets: tablet weight=250    mg, tablet hardness=8 kp, tablet thickness=0.185.″

The present invention has been described above with reference to theaccompanying drawings, in which preferred embodiments of the inventionare shown. Unless otherwise defined, all technical and scientific termsused herein are intended to have the same meaning as commonly understoodin the art to which this invention pertains and at the time of itsfiling. Although various methods and materials similar or equivalent tothose described herein can be used in the practice or testing of thepresent invention, suitable methods and materials are described. Theskilled should understand that the methods and materials used anddescribed are examples and may not be the only ones suitable for use inthe invention.

Moreover, it should also be understood that any measurements, quantitiesor numerical figures expressed herein are intended to be approximate andnot an exact or critical figure unless expressly stated to the contrary.

Further, any publications, patent applications, patents, and otherreferences mentioned herein are incorporated by reference in theirentirety as if they were part of this specification. However, in case ofconflict, the present specification, including any definitions, willcontrol. In addition, as noted above, materials, methods and examplesgiven are illustrative in nature only and not intended to be limiting.

Accordingly, this invention may be embodied in many different forms andshould not be construed as limited to the illustrated embodiments setforth herein. Rather, these illustrated embodiments are provided so thatthis disclosure will be thorough, complete, and will convey the scope ofthe invention to those skilled in the art. Therefore, in thespecification set forth above there have been disclosed typicalpreferred embodiments of the invention, and although specific terms areemployed, the terms are used in a descriptive sense only and not forpurposes of limitation. The invention has been described in some detail,but it will be apparent that various modifications and changes can bemade within the spirit and scope of the invention as described in theforegoing specification and as defined in the appended claims.

TABLE 1 Formulations of 2 mg Melatonin Extended Release TabletDevelopment Prototypes % w/w Lot # CYV45-002- Ingredient 004 007 011 01221A/B 030 48A 48B Intra-granular Components Melatonin 0.8 (2 mg/tablet)Hypromellose 30 K4M Hypromellose 30 15M Hypromellose 30 K100LVHypromellose 30 30 30 20 30 E50 PEG 3350 5 PEG 8000 5 5 5 Citric Acid 1616 32 32 27 27 27 17 Starch 28 28 12 12 12 12 12 12 MCC 12.2 Extra-ProSolv HD90 12 12 12 12 12 12 22 12 granular Citric acid 10 ComponentsCabosil 0.5 Mag Stearate 0.5 Total 100%

TABLE 2 Quantitative Formula for Melatonin 2 mg ER Tablets LeadPrototype Lot # 11216-048A Materials 2 mg Vendor/Lot # FunctionalityTablet % w/w g/Batch Gran. Soln Melatonin melatonin 2.0 0.8 2.4(Nutri-Force lot # 81120) Purified Water¹ Granulation NA NA 15 g for PEGsolvent solution + 33.5 g for granulation Polyethylene GlycolSolubilizer 12.5 5.0 15 PEG8000 (Dow) Intragranular MicrocrystallineDiluent 30.5 12.2 36.6 Cellulose, NF Avicel PH-101 (FMC) Citric AcidMonohydrate Acidifier 67.5 27.0 81 Powder (Spectrum) Co-processed StarchDiluent/ 30 12.0 36 Starcap 1500 binder (Colorcon) HypromelloseMethocel ™ Matrix Polymer 50.0 20.0 60 E50 (Dow) Extragranular² ProSolvHD90 (JRS Diluent 55.0 22.0 66 Pharma) Cab-O-Sil M-5P (Cabot) Glidant1.25 0.5 1.5^(b) Magnesium Stearate Lubricant 1.25 0.5 1.5^(b) (Veg.Source, Product Code 2257), NF/EP/JP Total 250.0 100.0% 300 g ¹Removedupon drying ²Adjusted based on granulation yield

TABLE 3 Melatonin 2 mg Extended Release Prototype Final Blend PhysicalProperties Bulk Density 0.43 g/mL Tap Density 0.50 g/mL Compressibility14.4% Flodex Flow 16 mm critical orifice Sieve Analysis % Retained 600μm 19.8 425 μm 15.1 300 μm 10.0 180 μm 16.5 106 μm 20.6  45 μm 17.1 <45μm 0.1

TABLE 4 Properties of Melatonin 2 mg Extended Release Tablet- PrototypeLot CYV45-002-048A Property Results Tablet Press Eight station PicollaB/D press (one station used) Tablet Tooling FDL-041: 0.455″ × 0.190″capsule shaped, plain faced Tablet Press Speed 40 rpm Main compression4.2 kiloNewtons Force Precompression Not used Ejection Force 92 NewtonsMean Tablet 251 mg (range 249-253 mg % RSD = 0.5) weight* Mean Tablet3.9 (range 3.4-4.2, % RSD = 6.2) Hardness* Mean Tablet 0.196″ (range0.195-0.196″, % RSD = Thickness* 0.2) Tablet Friability 0.03% for 100drops *10 tablets chosen at random from compression of 300 g batch

TABLE 5 Melatonin Assay/Related Substances of 2 mg Melatonin ExtendedRelease Tablets Lot CYV45-002-048A Melatonin Assay 105.2% ReportableImpurities  0.18% @RRT 1.47 (>0.10%) Total Impurities  1.8%

TABLE 6 Composition of Final Tablet Materials 2 mg Vendor/Lot # Tablet %w/w g/Batch^(a) Purified Water NA^(a) NA^(a) 58 g for PEG solution + 157g for granulation^(a) Melatonin 2.0 0.8 8.0 PEG8000 12.5 5.0 50.0Microcrystalline 144.25 57.7 577.0 Cellulose, NF Avicel PH102 CitricAcid Powder 12.5 5.0 50.0 Hypromellose 75.0 30.0 300 Methocel ™ E50Cab-O-Sil Colloidal 1.25 0.5 5.0 Silicon Dioxide Magnesium Stearate 2.501.0 10.0 Total Prior to 250.0 100.0% 1000 g Coating ^(a)Water was usedas a solvent and granulation fluid and was removed during processing.

BIBLIOGRAPHY

Bénès, L., B. Claustyat, et al. (1997). “Transmucosal, oral controlledrelease, and transdermal drug administration in human subjects: Acrossover study with melatonin.” J Pharmaceutical Sci. 86(10):1115-1119.

He, H., Katsumura, Y. et al. (2005). In Japanese. Org. and Biomol.Chem., 3 (2005) 1568

Lee, B.-J., Keith Parrott, et al. (1995). “Design and evaluation of anoral controlled release delivery system for melatonin in humansubjects.” Int J Pharmaceuticals 124 (1995): 119-127.

Lee, B.-J., S.-G. Ryu, et al. (1999). “Formulation and releasecharacteristics of hydroxypropyl methylcellulose matrix tabletcontaining melatonin.” Drug Dev. and Ind. Pharmacy 25(4): 493-501.

Liu, Y.-Y., X. D. Fan, et al. (2006). “pH-responsive amphiphilichydrogel networks with IPN structure: A strategy for controlled drugrelease.” Int. J Pharmaceutics 308 (2006): 205-209.

McIntyre I. M, Norman, T. R., et al. (1987) “Melatonin Rhythym in HumanPlasma and Saliva,” Journal of Pineal Research 4 (1987): 177-183.

Mahal, H. S., Sharma, H. S. and Mukherjee, T. (1999). “Antioxidantproperties of Melatonin: A pulse radiolysis study.” Free Radical Biology& Medicine, 26(5/6): 557-565

Touitou, Y. (2001) “Human aging and melatonin. Clinical relevance”Experimental Gerontology 36 (2001): 1083-1100.

Tran, H. T. T., Tran, P. H. L. and Lee, B.-J. (2009) “New findings onmelatonin absorption and alterations by pharmaceutical excipients usingthe Ussing chamber technique with mounted rat gastrointestinal segments”Int. J Pharmaceutics 378 (2009): 9-16.

What is claimed is:
 1. A controlled-release melatonin-containing productcomprising: a composition comprising melatonin, a pH lowering agent, anda gel-forming forming polymer that, when said composition is ingested,forms an aqueous gel matrix having melatonin dissolved therein and aninternal pH of less than 4.4 in said aqueous gel matrix, wherein saidcomposition provides a first release dose of melatonin for assisting ininducement of sleep and a subsequent sustained release dose of melatoninfor assisting in sustaining sleep; and said composition is effective torelease approximately 50% of said melatonin in said composition into thegastrointestinal tract within approximately two hours after oralingestion.
 2. The product of claim 1, wherein said composition is intablet dosage form, multiparticulate-containing dosage form, or acombination thereof.
 3. The product of claim 1, wherein said compositionis effective to release substantially all of the remaining melatonin insaid composition into the gastrointestinal tract over approximatelythree to approximately ten hours after oral ingestion.
 4. The product ofclaim 1, wherein said composition is effective to release substantiallyall of the remaining melatonin in said composition into the lowergastrointestinal tract over approximately three to approximately tenhours after oral ingestion.
 5. The product of claim 1, wherein said pHlowering agent is an acid, acidic buffer, or a combination thereof. 6.The product of claim 1, wherein said internal pH is 2 to 4 in saidaqueous gel matrix.
 7. The product of claim 1, wherein said compositionfurther comprises at least one other active ingredient in addition tosaid melatonin.
 8. A controlled-release melatonin product comprising acompressed tablet comprising melatonin, citric acid, and a cellulosicpolymer that combine after ingestion to form an acidic hydrogel thatdissolves said melatonin and is effective to provide a first releasedose of melatonin for assisting in inducement of sleep and a subsequentsustained release dose of melatonin for assisting in sustaining sleepwhile in a human subject's gastrointestinal tract, wherein said tabletis effective to release approximately 50% of said melatonin in saidtablet into the gastrointestinal tract within approximately two hoursafter oral ingestion, wherein the amount of said citric acid issufficient to impart a pH of less than 4.4 to said hydrogel.
 9. Theproduct of claim 8, wherein said tablet is effective to releasesubstantially all of the remaining melatonin in said tablet into saidhuman subject's gastrointestinal tract over approximately three toapproximately ten hours after oral ingestion.
 10. The product of claim8, wherein said tablet is effective to release substantially all of theremaining melatonin in said tablet into said human subject's lowergastrointestinal tract over approximately three to approximately tenhours after oral ingestion.
 11. The product of claim 8, wherein theamount of said citric acid is sufficient to impart a pH of 2-4to saidhydrogel.
 12. The product of claim 8, wherein said tablet furthercomprises at least one other active ingredient in addition to saidmelatonin.
 13. A sleep-aid product comprising: a sleep-aid effectiveamount of a composition comprising melatonin, a gel-forming polymer, anda sufficient amount of at least one acidic moiety to impart a pH of 2-4to said gel-forming polymer after oral ingestion by a human subject;said gel-forming polymer and acidic moiety being effective to form a gelmatrix having said pH when said composition is in said human subject'sintestines for solubilizing said melatonin within said gel matrix; saidgel-forming polymer and acidic moiety also being effective to providesustained release of melatonin from said gel matrix for at least sixhours after oral ingestion.
 14. The product of claim 13, wherein saidcomposition is effective to release approximately 50% of said melatoninin said composition into said human subject's gastrointestinal tractwithin approximately two hours after oral ingestion.
 15. The product ofclaim 13, wherein said composition further comprises at least one otheractive ingredient in addition to said melatonin.
 16. The product ofclaim 13, wherein said sleep-aid effective amount includes 5 microgramsto 10 milligrams of said melatonin.
 17. The product of claim 13, whereinsaid composition is in tablet dosage form, multiparticulate-containingdosage form, or a combination thereof.
 18. The product of claim 14,wherein said composition is effective to release substantially all ofthe remaining melatonin in said composition into said human subject'sgastrointestinal tract within approximately ten hours after oralingestion.
 19. The product of claim 14, wherein said composition iseffective to release substantially all of the remaining melatonin insaid composition into said human subject's lower gastrointestinal tractwithin approximately ten hours after oral ingestion.
 20. The product ofclaim 13, wherein an amount of said acidic moiety is sufficient tomaintain said pH for at least 7 hours.
 21. The product of claim 13,wherein said acidic moiety is an acid, acidic buffer, or a combinationthereof.
 22. The product of claim 13, where said acidic moiety is anorganic acid.